Ion selective sorbents have been used in human therapy to correct disorders in electrolyte balance, in conditions such as hyperphosphatemia, hyperoxaluria, hypercalcemia, and hyperkalemia. Hyperphosphatemia occurs in patients with renal failure, whose kidneys no longer excrete enough phosphate ions to compensate exogenous phosphate uptake in the diet. This condition leads to high serum phosphate concentration and high calcium x phosphate product. Although the etiology is not fully demonstrated, high calcium x phosphate product has been held responsible for soft tissue calcification and cardiovascular disease. Cardiovascular disease is the cause of death in almost half of all dialysis patients.
Aluminum, calcium, and, more recently, lanthanum salts have been prescribed to control phosphate ion absorption in the gastrointestinal (GI) tract and restore systemic phosphate levels back to normal. However these salts liberate soluble aluminum and calcium cations in the GI tract, which are then partially absorbed into the blood stream. Aluminum absorption can cause serious side effects such as aluminum bone disease and dementia; high calcium uptake leads to hypercalcemia and puts patients at risk for coronary calcification.
Metal-free phosphate binders such as strong base ion-exchanger materials, Dowex and Cholestyramine resins, have been suggested for use as phosphate binders. However, their low capacity of binding requires high dosage that is not well tolerated by patients.
Amine functional polymers have been described as phosphate or oxalate binders. For example, see U.S. Pat. Nos. 5,985,938; 5,980,881; 6,180,094; 6,423,754; and PCT publication WO 95/05184. Renagel, a crosslinked polyallylamine resin, is a phosphate sequestering material introduced in the market as a metal-free phosphate binder. In vitro phosphate binding of Renagel is approximately 6 mmol/gm in water and 2.5 mmol/gm when measured in 100 mM sodium chloride and 20 mM phosphate at neutral pH. The recommended dosage for the targeted patient population is typically between 5 gms/day to 15 gms/day to keep the phosphate concentration below 6 mg/dL. Published phase I clinical trials on Renagel, performed on healthy volunteers, indicate that 15 gins of Renagel decrease the phosphate urinary excretion from a baseline of 25 mmole to 17 mmole, the difference being excreted in the feces as free and polymer-bound phosphate. From these data, the in vivo capacity range can be established at 0.5-1 mmol/gm, which is much less than the in vitro capacity of 6 mmol/gr measured in saline. Considering only the in vitro binding capacity of Renagel measured in saline, a dosage of 15 gm of phosphate binder would bind more than the entire phosphorous content of the average American diet, i.e. 37 mmol/day. The discrepancy between the in vitro binding capacity and the documented low in vivo binding capacity has a negative impact on the therapeutic benefit of the drug since more resin is needed to bring the serum phosphate to a safe range.
This loss of capacity of ion-exchange resins is not limited to Renagel when used in the complex environment of the GI tract environment. Although generally safe from a toxicological perspective, the large dose and inconvenience associated with taking multigram amounts of resin argues for the need to improve resin capacity. As an example, even in reported safety studies of the Renagel binder, patients have noted gastrointestinal discomfort at doses as low as 1.2-2.0 gm/day for an 8 week treatment period. Patients receiving 5.4 gm of Renagel/day were discontinued from treatment due to adverse events such as GI discomfort in 8.9% of the cases (Slatapolsky, et al Kidney Int. 55:299-307, 1999; Chertow, et al Nephrol Dial Transplant 14:2907-2914, 1999). Thus, an improvement in in vivo binding capacity that translates to lower, better tolerated dosing would be a welcome improvement in resin-based therapies.
As a result of these considerations there is still a great need for safe, high-capacity binders that selectively remove ions from the body with a lower drug dosage and a better patient compliance profile.
Patient compliance is recognized today as one of the main limiting factors for patients to comply with the K/DOQI recommendations: dose escalation implies that patients have to take ten 800 mg pills per day and beyond. Renagel pills take the form of swallowable tablets and are administered with a minimum of fluid, adding to the burden of ESRD patients who are under fluid restriction. More easy-to-take pharmaceutical formulation would be desirable: in particular chewable tablets are becoming more popular amongst the geriatric and pediatric population and in treatments requiring a large pill burden: chewable tablets allows greater strength pills and ultimately reduces the number of tablets per meal. Because the active contained in a chewable tablet is first dispersed under the effects of mastication and saliva before being swallowed, the requirements on both the shape and weight of the tablet are much less severe than those imposed on swallowable tablets: However, until now it was not possible to formulate a hydrogel such as Renagel in a chewable tablet because of the high swelling characteristics of that polymer: Renagel usually swells very rapidly up to about 10 times its weight in an isotonic solution. This has two much undesired consequences: firstly, while in the mouth the polymer will swell and give a very unpleasant feel (dry mouth, sensation of choking); secondly, even if patient overcomes the sensory in mouth, the administration of a swollen gel in the esophagus can be hazardous. Besides, it is also well known that highly swellable gels, when administered in the multi grams range, provoke side effects such as bloating, constipation or diarrhea.